Page 41 - NNS 2014 Program & Abstract Book

tested whether activation of the KOR is necessary to produce the adverse
effects of morphine using norBNI, a selective KOR antagonist. Subjects
received a moderate spinal contusion (T12), and an intrathecal cannula
was implanted. Baseline locomotor function (BBB) and pain reactivity
(tail-flick) were assessed 24 hours following injury. Subjects were then
pretreated with norBNI (0, .08, or .32 lmol), followed by morphine (0 or
.32 lmol). Pain reactivity was re-assessed 30 minutes after drug treat-
ment. Locomotor recovery was evaluated across a 21-day period, with
additional tests of motor and sensory function conducted after day 21.
Our results show that pretreatment with norBNI blocks the morphine-
induced effects on recovery in a dose-dependent manner. At higher doses,
norBNI eliminates morphine’s adverse effects on recovery, but analgesia
is also abolished. Conversely, at low doses, analgesia is maintained, but
the adverse effects persist. This suggests that activation of the KOR
system is necessary and sufficient for morphine-induced attenuation of
recovery. However, as the protective dose of norBNI also diminished
analgesic efficacy, simply blocking KOR activity is not sufficient for
improving the efficacy and safety of clinical opioid use. Further under-
standing of the specific molecular changes induced by KOR activation is
necessary to improve pain management strategies and facilitate func-
tional recovery after SCI. Research support: Grant DA-031197, NIDA
Drug Supply Program, & Mission Connect (TIRR Foundation).
Key words
KOR, locomotor function, norBNI, opioids
T1-20
AXONAL STRETCH INJURY RESULTS IN A POTENTIAL
REDISTRIBUTION OF PHOSPHORYLATED TAU FROM
AXONS TO THE SOMA AND DENDRITES
Dolle´, J.P., Jaye, A., Johnson, V.E., Smith, D.H.
University of Pennsylvania, Department of Neurosurgery,
Philadelphia, USA
Both single and repetitive traumatic brain injury (TBI) have been
shown to induce abnormal aggregation of hyperphosphorylated
tau comprising neurofibrillary tangles (NFTs), one of the hall-
mark pathologies of chronic traumatic encephalopathy. However,
it has remained unknown how the axonal protein, tau, accumulates
in the cell soma after TBI. Here, we examine the temporal effects
of traumatic axonal injury (TAI) on tau phosphorylation levels
within neuron compartments using a well-characterized in vitro
model.
Primary cortical neurons were grown on micropatterned deformable
silastic membranes, whereby a series of parallel 2 mm-long lanes
containing only axons spanned two populations of neuronal soma. The
axon only region was rapidly stretched via mechanical parameters
based on clinical TBI. Cells were immunocytochemically analyzed at
1, 24 and 48 hrs post injury for ankyrin-G, total tau and tau phos-
phoepitopes AT8, AT270 and S404.
By 1 hr following axonal stretch injury, decreases in axon initial
segment (AIS) length and axonal total and phospho-tau immunore-
activity levels were observed. Concomitantly, increases in total and
phospho-tau immunoreactivity levels were observed in the cell-soma
and dendrites. Cell-somal phospho-tau levels continued to increase
over 48 hrs post-injury. Translocation of phospho-tau S404 into den-
drites was observed within 1 hr, whereas phospho-tau AT8 was only
observed after 24 hrs. The protein synthesis inhibitor Emetine reduced
cell-somal increases in total and phospho-tau immunoreactivity levels.
Although specific mechanisms inducing the chronic formation of
post-traumatic NFTs remain elusive, the present data provides po-
tential sources of acute increases of phospho-tau in neuronal soma and
dendrites, including: 1) a reduction in the AIS diffusion barrier re-
sulting in a translocation of total tau/phospho-tau from the axon into
the soma, and 2) de novo tau protein synthesis and accumulation in
the soma.
Supported by DOD grant, PT110785 and NIH grant NS056202.
Key words
axon stretch, phosphorylated tau, traumatic axonal injury
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